The present invention relates to sulfide and disulfide compounds; compositions comprising the sulfide or disulfide compounds; and methods for treating or preventing a disease or disorder, for example, cardiovascular disease, dyslipidemia; dyslipoproteinemia; a disorder of glucose metabolism; Alzheimer""s Disease; Syndrome X; a peroxisome proliferator activated receptor-associated disorder; septicemia; a thrombotic disorder; obesity; pancreatitis; hypertension; renal disease; cancer; inflammation; and impotence. The compound of the invention can also treat or prevent inflammatory processes and diseases like gastrointestinal disease, irritable bowel syndrome (IBS), inflammatory bowel disease (Crohn""s Disease, ulcerative colitis), arthritis (rheumatoid arthritis, osteoarthritis), autoimmune disease (systemic lupus erythematosus, etc.), scleroderma, ankylosing spondylitis, gout and pseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis; infection and arthritis, juvenile rheumatoid arthritis, tendonitis, bursitis and other soft tissue rheumatism. The sulfide and disulfide compounds and compositions of the invention may also be used to reduce the fat content of meat in livestock and reduce the cholesterol content of eggs.
Obesity, hyperlipidemia, and diabetes have been shown to play a causal role in atherosclerotic cardiovascular diseases, which currently account for a considerable proportion of morbidity in Western society. Further, one human disease, termed xe2x80x9cSyndrome Xxe2x80x9d or xe2x80x9cMetabolic Syndromexe2x80x9d, is manifested by defective glucose metabolism (insulin resistance), elevated blood pressure (hypertension), and a blood lipid imbalance (dyslipidemia). See e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131.
The evidence linking elevated serum cholesterol to coronary heart disease is overwhelming. Circulating cholesterol is carried by plasma lipoproteins, which are particles of complex lipid and protein composition that transport lipids in the blood. Low density lipoprotein (LDL) and high density lipoprotein (HDL) are the major cholesterol-carrier proteins. LDL is believed to be responsible for the delivery of cholesterol from the liver, where it is synthesized or obtained from dietary sources, to extrahepatic tissues in the body. The term xe2x80x9creverse cholesterol transportxe2x80x9d describes the transport of cholesterol from extrahepatic tissues to the liver, where it is catabolized and eliminated. It is believed that plasma HDL particles play a major role in the reverse transport process, acting as scavengers of tissue cholesterol. HDL is also responsible for the removal of non-cholesterol lipid, oxidized cholesterol and other oxidized products from the bloodstream.
Atherosclerosis, for example, is a slowly progressive disease characterized by the accumulation of cholesterol within the arterial wall. Compelling evidence supports the belief that lipids deposited in atherosclerotic lesions are derived primarily from plasma apolipoprotein B (apo B)-containing lipoproteins, which include chylomicrons, CLDL, IDL and LDL. The apo B-containing lipoprotein, and in particular LDL, has popularly become known as the xe2x80x9cbadxe2x80x9d cholesterol. In contrast, HDL serum levels correlate inversely with coronary heart disease. Indeed, high serum levels of HDL are regarded as a negative risk factor. It is hypothesized that high levels of plasma HDL are not only protective against coronary artery disease, but may actually induce regression of atherosclerotic plaque (e.g., see Badimon et al., 1992, Circulation 86: (Suppl. III)86-94; Dansky and Fisher, 1999, Circulation 100:1762-3.). Thus, HDL has popularly become known as the xe2x80x9cgoodxe2x80x9d cholesterol.
The fat-transport system can be divided into two pathways: an exogenous one for cholesterol and triglycerides absorbed from the intestine and an endogenous one for cholesterol and triglycerides entering the bloodstream from the liver and other non-hepatic tissue.
In the exogenous pathway, dietary fats are packaged into lipoprotein particles called chylomicrons, which enter the bloodstream and deliver their triglycerides to adipose tissue for storage and to muscle for oxidation to supply energy. The remnant of the chylomicron, which contains cholesteryl esters, is removed from the circulation by a specific receptor found only on liver cells. This cholesterol then becomes available again for cellular metabolism or for recycling to extrahepatic tissues as plasma lipoproteins.
In the endogenous pathway, the liver secretes a large, very-low-density lipoprotein particle (VLDL) into the bloodstream. The core of VLDL consists mostly of triglycerides synthesized in the liver, with a smaller amount of cholesteryl esters either synthesized in the liver or recycled from chylomicrons. Two predominant proteins are displayed on the surface of VLDL, apolipoprotein B-100 (apo B-100) and apolipoprotein E (apo E), although other apolipoproteins are present, such as apolipoprotein CIII (apo CIII) and apolipoprotein CII (apo CII). When a VLDL reaches the capillaries of adipose tissue or of muscle, its triglyceride is extracted. This results in the formation of a new kind of particle called intermediate-density lipoprotein (IDL) or VLDL remnant, decreased in size and enriched in cholesteryl esters relative to a VLDL, but retaining its two apoproteins.
In human beings, about half of the IDL particles are removed from the circulation quickly, generally within two to six hours of their formation. This is because IDL particles bind tightly to liver cells, which extract IDL cholesterol to make new VLDL and bile acids. The IDL not taken up by the liver is catabolized by the hepatic lipase, an enzyme bound to the proteoglycan on liver cells. Apo E dissociates from IDL as it is transformed to LDL. Apo B-100 is the sole protein of LDL.
Primarily, the liver takes up and degrades circulating cholesterol to bile acids, which are the end products of cholesterol metabolism. The uptake of cholesterol-containing particles is mediated by LDL receptors, which are present in high concentrations on hepatocytes. The LDL receptor binds both apo E and apo B-100 and is responsible for binding and removing both IDL and LDL from the circulation. In addition, remnant receptors are responsible for clearing chylomicrons and VLDL remnants i.e., IDL).
However, the affinity of apo E for the LDL receptor is greater than that of apo B-100. As a result, the LDL particles have a much longer circulating life span than IDL particles; LDL circulates for an average of two and a half days before binding to the LDL receptors in the liver and other tissues. High serum levels of LDL, the xe2x80x9cbadxe2x80x9d cholesterol, are positively associated with coronary heart disease. For example, in atherosclerosis, cholesterol derived from circulating LDL accumulates in the walls of arteries. This accumulation forms bulky plaques that inhibit the flow of blood until a clot eventually forms, obstructing an artery and causing a heart attack or stroke.
Ultimately, the amount of intracellular cholesterol liberated from the LDL controls cellular cholesterol metabolism. The accumulation of cellular cholesterol derived from VLDL and LDL controls three processes. First, it reduces the cell""s ability to make its own cholesterol by turning off the synthesis of HMGCoA reductase, a key enzyme in the cholesterol biosynthetic pathway. Second, the incoming LDL-derived cholesterol promotes storage of cholesterol by the action of chlolesterol acyltransferase (xe2x80x9cACATxe2x80x9d), the cellular enzyme that converts cholesterol into cholesteryl esters that are deposited in storage droplets. Third, the accumulation of cholesterol within the cell drives a feedback mechanism that inhibits cellular synthesis of new LDL receptors. Cells, therefore, adjust their complement of LDL receptors so that enough cholesterol is brought in to meet their metabolic needs, without overloading (for a review, see Brown and Goldstein, In, The Pharmacological Basis Of Therapeutics, 8th Ed., Goodman and Gilman, Pergamon Press, New York, 1990, Ch. 36, pp. 874-896).
High levels of apo B-containing lipoproteins can be trapped in the subendothelial space of an artery and undergo oxidation. The oxidized lipoprotein is recognized by scavenger receptors on macrophages. Binding of oxidized lipoprotein to the scavenger receptors can enrich the macrophages with cholesterol and cholesteryl esters independently of the LDL receptor. Macrophages can also produce cholesteryl esters by the action of ACAT. LDL can also be complexed to a high molecular weight glycoprotein called apolipoprotein(a), also known as apo(a), through a disulfide bridge. The LDL-apo(a) complex is known as Lipoprotein(a) or Lp(a). Elevated levels of Lp(a) are detrimental, having been associated with atherosclerosis, coronary heart disease, myocardial infarction, stroke, cerebral infarction, and restenosis following angioplasty.
Peripheral (non-hepatic) cells predominantly obtain their cholesterol from a combination of local synthesis and uptake of preformed sterol from VLDL and LDL. Cells expressing scavenger receptors, such as macrophages and smooth muscle cells, can also obtain cholesterol from oxidized apo B-containing lipoproteins. In contrast, reverse cholesterol transport (RCT) is the pathway by which peripheral cell cholesterol can be returned to the liver for recycling to extrahepatic tissues, hepatic storage, or excretion into the intestine in bile. The RCT pathway represents the only means of eliminating cholesterol from most extrahepatic tissues and is crucial to maintenance of the structure and function of most cells in the body.
The enzyme in blood involved in the RCT pathway, lecithin:cholesterol acyltransferase (LCAT), converts cell-derived cholesterol to cholesteryl esters, which are sequestered in HDL destined for removal. LCAT is produced mainly in the liver and circulates in plasma associated with the HDL fraction. Cholesterol ester transfer protein (CETP) and another lipid transfer protein, phospholipid transfer protein (PLTP), contribute to further remodeling the circulating HDL population (see for example Bruce et al., 1998, Annu. Rev. Nutr. 18:297-330). PLTP supplies lecithin to HDL, and CETP can move cholesteryl ester made by LCAT to other lipoproteins, particularly apoB-containing lipoproteins, such as VLDL. HDL triglyceride can be catabolized by the extracellular hepatic triglyceride lipase, and lipoprotein cholesterol is removed by the liver via several mechanisms.
Each HDL particle contains at least one molecule, and usually two to four molecules, of apolipoprotein (apo A-I). Apo A-I is synthesized by the liver and small intestine as preproapolipoprotein which is secreted as a proprotein that is rapidly cleaved to generate a mature polypeptide having 243 amino acid residues. Apo A-I consists mainly of a 22 amino acid repeating segment, spaced with helix-breaking proline residues. Apo A-I forms three types of stable structures with lipids: small, lipid-poor complexes referred to as pre-beta-1 HDL; flattened discoidal particles, referred to as pre-beta-2 HDL, which contain only polar lipids (e.g., phospholipid and cholesterol); and spherical particles containing both polar and nonpolar lipids, referred to as spherical or mature HDL (HDL3 and HDL2). Most HDL in the circulating population contains both apo A-I and apo A-II, a second major HDL protein. This apo A-I- and apo A-II-containing fraction is referred to herein as the AI/AII-HDL fraction of HDL. But the fraction of HDL containing only apo A-I, referred to herein as the AI-HDL fraction, appears to be more effective in RCT. Certain epidemiologic studies support the hypothesis that the AI-HDL fraction is antiartherogenic (Parra et al., 1992, Arterioscler. Thromb. 12:701-707; Decossin et al., 1997, Eur. J. Clin Invest. 27:299-307).
Although the mechanism for cholesterol transfer from the cell surface is unknown, it is believed that the lipid-poor complex, pre-beta-1 HDL, is the preferred acceptor for cholesterol transferred from peripheral tissue involved in RCT. Cholesterol newly transferred to pre-beta-1 HDL from the cell surface rapidly appears in the discoidal pre-beta-2 HDL. PLTP may increase the rate of disc formation (Lagrost et al., 1996, J. Biol. Chem. 271:19058-19065), but data indicating a role for PLTP in RCT is lacking. LCAT reacts preferentially with discoidal and spherical HDL, transferring the 2-acyl group of lecithin or phosphatidylethanolamine to the free hydroxyl residue of fatty alcohols, particularly cholesterol, to generate cholesteryl esters (retained in the HDL) and lysolecithin. The LCAT reaction requires an apoliprotein such apo A-I or apo A-IV as an activator. ApoA-I is one of the natural cofactors for LCAT. The conversion of cholesterol to its HDL-sequestered ester prevents re-entry of cholesterol into the cell, resulting in the ultimate removal of cellular cholesterol. Cholesteryl esters in the mature HDL particles of the AI-HDL fraction are removed by the liver and processed into bile more effectively than those derived from the AI/AII-HDL fraction. This may be due, in part, to the more effective binding of AI-HDL to the hepatocyte membrane. Several HDL receptor receptors have been identified, the most well characterized of which is the scavenger receptor class B, type I (SR-BI) (Acton et al., 1996, Science 271:518-520). The SR-BI is expressed most abundantly in steroidogenic tissues (e.g., the adrenals), and in the liver (Landshulz et al., 1996, J. Clin. Invest. 98:984-995; Rigotti et al., 1996, J. Biol. Chem. 271:33545-33549). Other proposed HDL receptors include HB1 and HB2 (Hidaka and Fidge, 1992, Biochem J. 15:161-7; Kurata et al., 1998, J. Atherosclerosis and Thrombosis 4:112-7).
While there is a consensus that CETP is involved in the metabolism of VLDL- and LDL-derived lipids, its role in RCT remains controversial. However, changes in CETP activity or its acceptors, VLDL and LDL, play a role in xe2x80x9cremodelingxe2x80x9d the HDL population. For example, in the absence of CETP, the HDL becomes enlarged particles that are poorly removed from the circulation (for reviews on RCT and HDLs, see Fielding and Fielding, 1995, J. Lipid Res. 36:211-228; Barrans et al., 1996, Biochem. Biophys. Acta. 1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol. 17:1053-1059).
HDL is not only involved in the reverse transport of cholesterol, but also plays a role in the reverse transport of other lipids, i.e., the transport of lipids from cells, organs, and tissues to the liver for catabolism and excretion. Such lipids include sphingomyelin, oxidized lipids, and lysophophatidylcholine. For example, Robins and Fasulo (1997, J. Clin. Invest. 99:380-384) have shown that HDL stimulates the transport of plant sterol by the liver into bile secretions.
Peroxisome proliferators are a structurally diverse group of compounds that, when administered to rodents, elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes required for the xcex2-oxidation cycle (Lazarow and Fujiki, 1985, Ann. Rev. Cell Biol. 1:489-530; Vamecq and Draye, 1989, Essays Biochem. 24:1115-225; and Nelali et al., 1988, Cancer Res. 48:5316-5324). Chemicals included in this group are the fibrate class of hypolipidermic drugs, herbicides, and phthalate plasticizers (Reddy and Lalwani, 1983, Crit. Rev. Toxicol. 12:1-58). Peroxisome proliferation can also be elicited by dietary or physiological factors, such as a high-fat diet and cold acclimatization.
Insight into the mechanism whereby peroxisome proliferators exert their pleiotropic effects was provided by the identification of a member of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green, 1990, Nature 347:645-650). This receptor, termed peroxisome proliferator activated receptor xcex1 (PPARxcex1), was subsequently shown to be activated by a variety of medium and long-chain fatty acids. PPARxcex1 activates transcription by binding to DNA sequence elements, termed peroxisome proliferator response elements (PPRE), in the form of a heterodimer with the retinoid X receptor (RXR). RXR is activated by 9-cis retinoic acid (see Kliewer et al., 1992, Nature 358:771-774; Gearing et al., 1993, Proc. Natl. Acad. Sci. USA 90:1440-1444, Keller et al., 1993, Proc. Natl. Acad. Sci. USA 90:2160-2164; Heyman et al., 1992, Cell 68:397-406, and Levin et al., 1992, Nature 355:359-361). Since the discovery of PPARxcex1, additional isoforms of PPAR have been identified, e.g., PPARxcex2, PPARxcex3 and PPARxcex4, which have similar functions and are similarly regulated.
PPREs have been identified in the enhancers of a number of gene-encoding proteins that regulate lipid metabolism. These proteins include the three enzymes required for peroxisomal xcex2-oxidation of fatty acids; apolipoprotein A-I; medium-chain acyl-CoA dehydrogenase, a key enzyme in mitochondrial xcex2-oxidation; and aP2, a lipid binding protein expressed exclusively in adipocytes (reviewed in Keller and Whali, 1993, TEM, 4:291-296; see also Staels and Auwerx, 1998, Atherosclerosis 137 Suppl:S19-23). The nature of the PPAR target genes coupled with the activation of PPARs by fatty acids and hypolipidemic drugs suggests a physiological role for the PPARs in lipid homeostasis.
None of the commercially available cholesterol management drugs has a general utility in regulating lipid, lipoprotein, insulin and glucose levels in the blood. Thus, compounds that have one or more of these utilities are clearly needed. Further, there is a clear need to develop safer drugs that are efficacious at lowering serum cholesterol, increasing HDL serum levels, preventing coronary heart disease, and/or treating existing disease such as atherosclerosis, obesity, diabetes, and other diseases that are affected by lipid metabolism and/or lipid levels. There is also a clear need to develop drugs that may be used with other lipid-altering treatment regimens in a synergistic manner. There is still a further need to provide useful therapeutic agents whose solubility and Hydrophile/Lipophile Balance (HLB) can be readily varied.
Citation or identification of any reference in Section 2 of this application is not an admission that such reference is available as prior art to the present invention.
In one embodiment, the invention relates to a compound of the formula 1: 
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, stereoisomer, diastereomer, geometric isomer or mixtures thereof wherein:
(a) each occurrence of Z is independently CH2, CHxe2x95x90CH, or phenyl, where each occurrence of m is independently an integer ranging from 1 to 9, but when Z is phenyl then its associated m is 1:
(b) G is (CH2)x, where x is 2, 3, or 4, CH2CHxe2x95x90CHCH2, CHxe2x95x90CH, CH2-phenyl-CH2, or phenyl;
(c) W1 and W2 are independently L, V, C(R1)(R2)xe2x80x94(CH2)nxe2x80x94C(R3)(R4)xe2x80x94(CH2)nxe2x80x94Y, or C(R1)(R2)xe2x80x94(CH2)cxe2x80x94V where c is 1 or 2 and n is an integer ranging from 0 to 4;
(d) each occurrence of R1 or R2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or when one or both of W1 and W2 is C(R1)(R2)xe2x80x94(CH2)cxe2x80x94C(R3)(R4)xe2x80x94Y, then R1 and R2 can both be H to form a methylene group;
(e) R3 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(f) R4 is OH, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, phenyl, benzyl, Cl, Br, CN, NO2, or CF3;
(g) L is C(R1)(R2)xe2x80x94(CH2)nxe2x80x94Y where n is an integer from 0 to 4;
(h) V is 
(h) each occurrence of Y is independently OH, COOH, CHO, COOR5, SO3H, 
xe2x80x83where
(i) R5 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups,
(ii) each occurrence of R6 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, (C1-C6) alkoxy, or phenyl groups; and
(iii) each occurrence of R7 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl.
xe2x80x83and preferably, that:
(i) if G is (CH2)x, x is 2, each occurrence of Z is CH2, each occurrence of m is 1, and W1 is of the structure 
xe2x80x83then W2 is not the same as W1;
(ii) if G is (CH2)x, x is 2, each occurrence of Z is CH2, each occurrence of m is 3, and W1 xe2x80x94C(CH3)2CO2CH3, then W2 is not the same as W1;
(iii) if G is (CH2)x, x is 3, each occurrence of Z is CH2, each occurrence of m is 5, and W1 xe2x80x94C(CH3)2CO2CH3, then W2 is not the same as W1;
(iv) if G is (CH2)x, x is 3, each occurrence of Z is CH2, each occurrence of m is 5, and W1 xe2x80x94CCl2CO2CH3, then W2 is not the same as W1; and
(v) if G is phenyl, each occurrence of Z is CH2, each occurrence of m is 4, and W1 is of the structure 
then W2 is not the same as W1.
In another embodiment, the invention relates to a compound of the formula Ia: 
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemate or mixture of steroisomers thereof, wherein
(a) each occurrence of Z is independently CH2 or CHxe2x95x90CH, wherein each occurrence of m is independently an integer ranging from 1 to 9;
(b) G is (CH2)x, CH2CHxe2x95x90CHCH2, or CHxe2x95x90CH, where x is 2, 3, or 4;
(c) W1 and W2 are independently L, V, or C(R1)(R2)xe2x80x94(CH2)cxe2x80x94V, where c is 1 or 2;
(d) each occurrence of R1 and R2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl;
(e) L is C(R1)(R2)xe2x80x94(CH2)nxe2x80x94Y, where n is an integer ranging from 0 to 4;
(f) V is 
(g) each occurrence of Y is independently OH, COOH, CHO, COOR3, SO3H, 
xe2x80x83where
(i) R3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups,
(ii) each occurrence of R4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, C1-C6 alkoxy, or phenyl groups; and
(iii) each occurrence of R5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C1-C6)alkynyl.
xe2x80x83and preferably, that:
(i) if x is 2, each occurrence of Z is CH2, each occurrence of m is 1, and W1 is of the structure 
xe2x80x83then W2 is not the same as W1;
(ii) if x is 2, each occurrence of Z is CH2, each occurrence of m is 3, and W1 xe2x80x94C(CH3)2CO2CH3, then W2 is not the same as W1;
(iii) if x is 3, each occurrence of Z is CH2, each occurrence of m is 5, and W1 xe2x80x94C(CH3)2CO2CH3, then W2 is not the same as W1; and
(iv) if x is 3, each occurrence of Z is CH2, each occurrence of m is 5, and W1 xe2x80x94CCl2CO2CH3, then W2 is not the same as W1.
Preferably, in formula Ia each occurrence of Y is independently OH, COOR3, or COOH.
In yet another embodiment, the invention relates to a compound of the formula Ib 
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemate or mixture of steroisomers thereof, wherein:
(a) each occurrence of m is independently an integer ranging from 1 to 9;
(b) x is 2, 3, or 4;
(c) each occurrence of n is independently an integer ranging from 0 to 4;
(d) each occurrence of R1 and R2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl; and
(e) each occurrence of Y is independently OH, COOH, CHO, COOR3, SO3H, 
xe2x80x83where
(i) R3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups,
(ii) each occurrence of R4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, C1-C6 alkoxy, or phenyl groups; and
(iii) each occurrence of R5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl.
xe2x80x83and preferably, that:
(i) if x is 2, each occurrence of m is 1, and W1 is of the structure 
xe2x80x83then W2 is not the same as W1;
(ii) if x is 2, each occurrence of Z is CH2, each occurrence of m is 3, and W1 xe2x80x94C(CH3)2CO2CH3, then W2 is not the same as W1;
(iii) if x is 3, each occurrence of Z is CH2, each occurrence of m is 5, and W1 xe2x80x94C(CH3)2CO2CH3, then W2 is not the same as W1; and
(iv) if x is 3, each occurrence of Z is CH2, each occurrence of m is 5, and W1 xe2x80x94CCl2CO2CH3, then W2 is not the same as W1.
Preferably in formula Ib, each occurrence of Y is independently OH, COOR3, or COOH.
In still another embodiment, the invention relates to a compound of the formula Ic 
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemate or mixture of steroisomers thereof, wherein:
(a) each occurrence of m is an independent integer ranging from 1 to 9;
(b) x is 2, 3, or 4;
(c) V is 
xe2x80x83and preferably, that:
(i) if G is (CH2)x, x is 2, each occurrence of Z is CH2, each occurrence of m is 1, and W1 is of the structure 
xe2x80x83then W2is not the same as W1;
(ii) if x is 2, each occurrence of Z is CH2, each occurrence of m is 3, and W1 xe2x80x94C(CH3)2CO2CH3, then W2 is not the same as W1;
(iii) if x is 3, each occurrence of Z is CH2, each occurrence of m is 5, and W1 xe2x80x94C(CH3)2CO2CH3, then W2 is not the same as W1; and
(iv) if x is 3, each occurrence of Z is CH2, each occurrence of m is 5, and W1 xe2x80x94CCl2CO2CH3, then W2 is not the same as W1.
In another embodiment, the invention relates to a compound of the formula II: 
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemate or mixture of stereoisomers thereof, wherein
(a) each occurrence of R1 or R2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, benzyl, or R1 or R2 are both H, or the carbon to which they are both attached are taken together to form (C3-C7)cycloalkyl group;
(b) each occurrence of n is independently an integer ranging from 0 to 4;
(c) each occurrence of m is independently an integer ranging from 1 to 5;
(d) W1 and W2 are independently CH2OH, COOH, CHO, OC(O)R3, C(O)OR3, SO3H, 
xe2x80x83where
(i) R3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups,
(ii) each occurrence of R4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, C1-C6 alkoxy, or phenyl groups; and
(iii) each occurrence of R5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl.
In another embodiment, the invention relates to a compound of the formula IIa: 
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemate or mixture of steroisomers thereof, wherein
(a) R1 and R2 are OH, COOH, CHO, COOR7, SO3H, 
xe2x80x83where
(i) R7 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups;
(ii) each occurrence of R8 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, C1-C6 alkoxy, or phenyl groups;
(iii) each occurrence of R9 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl;
(b) R3 and R4 are (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl;
(c) R5 and R6 are H, halogen, (C1-C4)alkyl, (C1-C4)alkoxy, (C6)aryloxy, CN, NO2, N(R5xe2x80x2)2 where R5 and R5xe2x80x2are each independently H, (C1-C4)alkyl, phenyl, or benzyl;
(d) each occurrence of m is independently an integer ranging from 1 to 5;
(a) each occurrence of n is independently an integer ranging from 0 to 4; and
(b) C*1 and C*2 represent independent chiral-carbon centers.
Preferred compounds of formula IIa are those wherein each occurrence of R1 and R2 is independently OH, COOR7, or COOH.
Other preferred compounds of formula IIa are those wherein m is 0.
Other preferred compounds of formula IIa are those wherein m is 1.
Other preferred compounds of formula IIa are those wherein R1 and/or R2 is C(O)OH or CH2OH.
Other preferred compounds of formula IIa are those wherein R3 and R4 are each independently (C1-C6) alkyl.
Other preferred compounds of formula IIa are those wherein R3 and R4 are each methyl.
Other preferred compounds of formula IIa are those wherein C*1 is of the stereochemical configuration R or substantially R.
Other preferred compounds of formula IIa are those wherein C*1 is of the stereochemical configuration S or substantially S.
Other preferred compounds of formula IIa are those wherein C*2 is of the stereochemical configuration R or substantially R.
Other preferred compounds of formula IIa are those wherein C*2 is of the stereochemical configuration S or substantially S. stereochemical configuration S or substantially S.
In a particular embodiment, compounds of formula IIa are those wherein C*1 C*2 are of the stereochemical configuration (S1,S2) or substantially (S1,S2).
In another particular embodiment, compounds of formula IIa are those wherein C*1 C*2 are of the stereochemical configuration (S1,R2) or substantially (S1,R2).
In another particular embodiment, compounds of formula IIa are those wherein C*1 C*2 are of the stereochemical configuration (R1,R2) or substantially (R1,R2).
In another particular embodiment, compounds of formula IIa are those wherein C*1 C*2 are of the stereochemical configuration (R1,S2) or substantially (R1,S2).
In yet another embodiment, the invention relates to a compound of the formula III 
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemate or mixture of steroisomers thereof, wherein:
(a) each occurrence of Z is independently CH2, CHxe2x95x90CH, or phenyl, where each occurrence of m is independently an integer ranging from 1 to 5, but when Z is phenyl then its associated m is 1;
(b) G is (CH2)x, CH2CHxe2x95x90CHCH2, CHxe2x95x90CH, CH2-phenyl-CH2, or phenyl, where x is an integer ranging from 1 to 4;
(c) W1 and W2 are independently C(R1)(R2)xe2x80x94(CH2)nxe2x80x94Y; 
(d) each occurrence of n is independently an integer ranging from 0 to 4;
(e) R1 and R2 are independently (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl or R1 and R2 are both H;
(f) Y is OH, COOH, CHO, COOR3, SO3H, 
xe2x80x83where
(i) R3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups,
(ii) each occurrence of R4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, C1-C6 alkoxy, or phenyl groups,
(iii) each occurrence of R5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; and
(g) each occurrence of p is independently 0 or 1 where the broken line represents an optional presence of one or more additional carbon-carbon bonds that when present complete one or more carbon-carbon double bonds; and
Preferably in formula III, each occurrence of W1 and W2 is an independent C(R1)(R2)xe2x80x94(CH2)nxe2x80x94Y group and each occurrence of Y is independently OH, COOR3, or COOH.
In yet another embodiment, the invention relates to a compound of the formula IIIa: 
or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, enantiomer, diastereomer, racemate or mixture of steroisomers thereof, wherein
(a) each occurrence of m is independently an integer ranging from 1 to 5;
(b) x is an integer ranging from 1 to 4;
(c) W1 and W2 are independently C(R1)(R2)xe2x80x94(CH2)nxe2x80x94Y; 
(d) n is an integer ranging from 0 to 4;
(e) each occurrence of R1 or R2 is independently (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)alkynyl, phenyl, or benzyl;
(f) Y is OH, COOH, CHO, COOR3, SO3H, 
xe2x80x83where
(i) R3 is (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, or benzyl and is unsubstituted or substituted with one or more halo, OH, (C1-C6)alkoxy, or phenyl groups,
(ii) each occurrence of R4 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl and is unsubstituted or substituted with one or two halo, OH, C1-C6 alkoxy, or phenyl groups,
(iii) each occurrence of R5 is independently H, (C1-C6)alkyl, (C2-C6)alkenyl, or (C2-C6)alkynyl; and
(g) each occurrence of p is independently 0 or 1.
and preferably, that if x is 1 each occurrence of m is 1, and W1 is CH2OH, then W2 is not the same as W1.
Preferably in compound IIIa, W1 and W1 are independent C(R1)(R2)xe2x80x94(CH2)nxe2x80x94Y groups and each occurrence of Y is independently OH, COOR3, or COOH.
The compounds of the invention are useful in medical applications for treating or preventing cardiovascular diseases, dyslipidemias, dyslipoproteinemias, disorders of glucose metabolism, Alzheimer""s Disease, Syndrome X, PPAR-associated disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal diseases, cancer, inflammation, and impotence. As used herein, the phrase xe2x80x9ccompounds of the inventionxe2x80x9d means, collectively, the compounds of formulas I, II, and III and pharmaceutically acceptable salts, hydrates, solvates, and clathrates, enantiomers, diastereomer, racemates or mixtures of steroisomers thereof. Compounds of formula I encompass subgroup formulas Ia Ib, and Ic. Compounds of formula II encompass the subgroup of formula IIa, and compounds of formula III encompass subgroup of formula IIIa. Thus, xe2x80x9ccompound of the inventionxe2x80x9d collectively means compound of formulas I, Ia, Ib, Ic, II, IIa, III, and IIIa and pharmaceutically acceptable salts, hydrates, solvates, and clathrates, enantiomers, diastereomers, racemates or mixtures of steroisomers thereof. The compounds of the invention are identified herein by their chemical structure and/or chemical name. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound""s identity.